Therapeutic composition comprising 2, 5, 8-trimethylchromone



United States Patent THERAPEUTIC COMPOSITION COMPRISING 2,5,8-TRIMETHYLCHROMONE Georg E. Cronheim, Bristol, Va., and Norman H. Leake and Marvel L. Fielden, Bristol, Tenn., assignors to The S. E. Massengill Company, Bristol, Tenn, a corporation of Tennessee No Drawing. Application December 12, 1951, Serial No. 261,386

4 Claims. (Cl. 16765) This invention relates to new therapeutic compositions.

The object of this invention is to provide an improved therapeutic composition which is highly potent as a cardiac vasodilator and which is non-toxic even in large therapeutic doses.

Other objects and advantages will become obvious from the following detailed description.

We have discovered that 2,5,8-trimethylchromonc is highly effective as a cardiac vasodilator and is substantially non-toxic even in amounts considerably larger than normal therapeutic dosages. It is many times more potent than khellin, which has been employed clinically because of its profound dilaitng eiiect 0n the coronary arteries. The relative potency of khellin and 2,5,8-trimethylehromone is illustrated by the typical comparative test results shown in the table.

In this test series, the cardiac activity of khellin and of 2.5.8-trimethylchromone was compared according to a modified Langendorif technique using isolated rabbit hearts. The khellin was added to the blood before it entered the heart in an amount suflicient to give a concentration of 1 to 30,000. The amount of 2,5,8-trimethylchromone added provided a blood concentration of l to 300,000. The volume of blood flowing through the heart during a two minute period was measured before addition of the drug as a control to determine normal flow and after addition of the drug to determine its dilating effect in terms of increased volume flow. The difierence between the control volume and the test volume is expressed as percentage increase.

TABLE Control and test volumes of blood through an isolated rabbit heart during a 2-minute period The percentage increase of blood flow produced by the 2,5,8-trimethylchromone was almost as great as that caused by the khellin despite the fact that the former was employed in one tenth the concentration of the latter. In general, 2,5,8-trimethylchromone is about 9 to 10 times as potent as khellin.

The acute toxicity of 2,5,8-trimethylchromone is very low, being about one tenth that of khellin. Khellin frequently produces undesirable side reactions such as nausea, constipation, lightheadedness, dizziness, diarrhea and sometimes also urticaria and dermatitis, the incidence of which increases with larger doses. Furthermore, the drug is cumulative since elimination from the body is slow. As a result administration of khellin must be exceedingly cautious. On the other hand, the much greater potency and lower toxicity of 2,5,8-trimethylchromone permits more effective and safer therapeusis.

The 2,5,8-trimethylchromone is preferably administered orally and in predetermined dosage as, for example, in the form of tablets, capsules and the like. Because of its high potency, therapeutic doses of the drug are very small, generally ranging in the neighborhood of a few milligrams, and must be measured with great accuracy. Quantities as small as 2 to 3 milligrams are therapeutically effective. To ensure accurate dosage, it is essential that the drug be admixed with an inert, solid diluent. Any diluent may be employed for our purpose so long as it is inert and innocuous such as milk sugar, starch, bentonite and the like. Any proportion of diluent to drug may be used so long as it is incorporated in sufiicient amount to ensure accurately measurable and easily dispensible doses.

Although this invention has been described with reference to illustrative embodiments thereof, it will be apparent to those skilled in the art that it may be embodied in other forms but within the scope of the appended claims.

We claim:

1. A therapeutic composition in dosage unit form comprising 2,5,8-trimethylchromone as active therapeutic component in amount comprising at least about 2 milligrams per dosage unit in admixture with a solid, pharmaceutical carrier.

2. A therapeutic composition comprising 2,5,8-timethylchromone as active therapeutic component in amount comprising at least about 2 milligrams in admixture with milk sugar.

3. A therapeutic composition in dosage unit form comprising 2,5,8-trimethylchromone as active therapeutic component in amount comprising at least about 2 milligrams per dosage unit in admixture with starch.

4. A therapeutic composition in dosage unit form comprising 2,5,8-trimethylchromone as active therapeutic component in amount comprising at least about 2 milligrams per dosage unit in admixture with bentonite.

References Cited in the file of this patent Goodall et al.: Chemical Abstracts, vol. 30 1936), pg. 4860.

Jongebreur: J. Pharm. and Pharmacology, vol. 3, No. 2, February 1951, p. 123.

Huttrer et al.: Chemical Rev., vol. 48, No. 3 June 1951, p. 573. 

1. A THERAPEUTIC COMPOSITION IN DOSAGE UNIT FORM COMPRISING 2,5,8-TRIMETHYLCHROMONC AS ACTIVE THERAPEUTIC COMPONENT IN AMOUNT COMPRISING AT LEAST ABOUT 2 MILLIGRAMS PER DOSAGE UNIT IN ADMIXTURE WITH A SOLID, PHARMACEUTICAL CARRIER. 